rs2302387

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000443.4(ABCB4):c.175C>T(p.Leu59Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,612,594 control chromosomes in the GnomAD database, including 24,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 5350 hom., cov: 32)

Exomes 𝑓: 0.15 ( 18873 hom. )

Consequence

ABCB4
NM_000443.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.790

Publications

44 publications found

Variant links:

Genes affected

ABCB4 (HGNC:45): (ATP binding cassette subfamily B member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This gene encodes a full transporter and member of the p-glycoprotein family of membrane proteins with phosphatidylcholine as its substrate. The function of this protein has not yet been determined; however, it may involve transport of phospholipids from liver hepatocytes into bile. Alternative splicing of this gene results in several products of undetermined function. [provided by RefSeq, Jul 2008]

ABCB4 Gene-Disease associations (from GenCC):

progressive familial intrahepatic cholestasis type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
gallbladder disease 1
Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
pancreatitis
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ABCB4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 7-87462869-G-A is Benign according to our data. Variant chr7-87462869-G-A is described in ClinVar as Benign. ClinVar VariationId is 256158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.79 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4 link	c.175C>T	p.Leu59Leu	synonymous_variant	Exon 4 of 28	ENST00000649586.2	NP_000434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2 link	c.175C>T	p.Leu59Leu	synonymous_variant	Exon 4 of 28		NM_000443.4	ENSP00000496956.2

Frequencies

GnomAD3 genomes

AF:

0.229

AC:

34844

AN:

151828

Hom.:

5330

Cov.:

show subpopulations

Gnomad AFR

AF:

0.442

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.160

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.133

Gnomad FIN

AF:

0.139

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.143

Gnomad OTH

AF:

0.198

GnomAD2 exomes

AF:

0.170

AC:

42718

AN:

251194

AF XY:

0.164

show subpopulations

Gnomad AFR exome

AF:

0.449

Gnomad AMR exome

AF:

0.168

Gnomad ASJ exome

AF:

0.188

Gnomad EAS exome

AF:

0.194

Gnomad FIN exome

AF:

0.139

Gnomad NFE exome

AF:

0.140

Gnomad OTH exome

AF:

0.165

GnomAD4 exome

AF:

0.152

AC:

222260

AN:

1460648

Hom.:

18873

Cov.:

AF XY:

0.151

AC XY:

109789

AN XY:

726670

show subpopulations

African (AFR)

AF:

0.449

AC:

14993

AN:

33390

American (AMR)

AF:

0.166

AC:

7431

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.188

AC:

4900

AN:

26124

East Asian (EAS)

AF:

0.223

AC:

8839

AN:

39672

South Asian (SAS)

AF:

0.140

AC:

12073

AN:

86208

European-Finnish (FIN)

AF:

0.139

AC:

7440

AN:

53408

Middle Eastern (MID)

AF:

0.213

AC:

1230

AN:

5766

European-Non Finnish (NFE)

AF:

0.140

AC:

155123

AN:

1111012

Other (OTH)

AF:

0.170

AC:

10231

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

8456

16913

25369

33826

42282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5828

11656

17484

23312

29140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.230

AC:

34914

AN:

151946

Hom.:

5350

Cov.:

AF XY:

0.226

AC XY:

16814

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.442

AC:

18309

AN:

41418

American (AMR)

AF:

0.160

AC:

2443

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.196

AC:

681

AN:

3468

East Asian (EAS)

AF:

0.201

AC:

1036

AN:

5160

South Asian (SAS)

AF:

0.132

AC:

637

AN:

4812

European-Finnish (FIN)

AF:

0.139

AC:

1465

AN:

10542

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.144

AC:

9751

AN:

67946

Other (OTH)

AF:

0.200

AC:

422

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1238

2475

3713

4950

6188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

332

664

996

1328

1660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.171

Hom.:

7675

Bravo

AF:

0.241

Asia WGS

AF:

0.188

AC:

655

AN:

3478

EpiCase

AF:

0.144

EpiControl

AF:

0.144

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 17, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cholestasis, intrahepatic, of pregnancy, 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Progressive familial intrahepatic cholestasis type 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

4.2

(source)

DANN

Benign

0.64

PhyloP100

0.79

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over